Annually over 2 million Americans are affected by critical care illnesses (CCI), with profound societal, medical and economic costs. The cumulative morbidity from post-CCI complications ranks 4th in overall mortality in the USA. A common denominator of CI (e.g. sepsis, trauma, and cardiopulmonary bypass (CPB)) is severe stress imposed on the immune system. We had believed that the host's body returns to pre-insult homeostasis, but emerging evidence suggests that recovery from a CI is lengthier than previously thought. Consequently, CI survivors suffer from recurrent infections (e.g. cytomegalovirus (CMV)) and progressive organ failure. Among many types of leukocytes, monocytes (MO) are pivotal in all aspects of the immune yet their functions can be easily disrupted resulting in anergy, pathogen/neoplasm tolerance and aberrant inflammation. All of these morbidities are seen in post-CCI/CPB individuals but it is poorly defined how abnormal MO characteristic are maintained long-term. We hypothesize that changes in epigenetic regulation of MO and their myeloid progenitors are pivotal in an acquired, long-term post-CCI/CPB MO immuno-aberration in certain individuals. Our preliminary data shows that ~30% of CPB patients exhibit a newly acquired defect in MO that lasts at least three months in vitro. This defect is related to a persistent secretion of macrophage colony stimulating factor (M-CSF) post-CCI and epigenetic aberration of master transcription factor Pu.1. The defect correlates with increased serum markers of inflammation (C-reactive protein (CRP), macrophage markers), and elevated titers of ?CMV antibodies. Our research plan focuses on three aims selected because of their novelty, applicability to real-life clinical condition, potential to build a fruitful research endeavor in a future and potential to correct the aberration Aim 1. Does CPB lead to persistent functional changes of MO associated with PU.1 activation Aim 2. Are persistent functional changes in MOs post-CPB maintained by regulation of PU.1 and downstream changes to the epigenome induced by PU.1 binding? Aim 3. Are persistent functional changes in MOs post-CPB maintained by regulation of PU.1 and downstream changes to the epigenome induced by PU.1 binding? Our study addresses clinically important questions about the chronic consequences of CI and long-term immune system regulation. The study is aligned with current trends in translational medicine. This proposal addresses a critical issue in health maintenance and provides a potential medical interventional strategy.